chr4-52038232-C-A

Variant names:

• chr4-52038232-C-A
• rs1448040082
• NM_000232.5:c.28G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000232.5(SGCB):​c.28G>T​(p.Glu10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000264 in 1,135,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). The gene SGCB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: SGCB NM_000232.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.615
• Publications: 0 publications found

Genes affected

SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

SGCB Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Specifications for SGCB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 89 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-52038232-C-A is Pathogenic according to our data. Variant chr4-52038232-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 534947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.28G>T	p.Glu10*	stop_gained	Exon 1 of 6	NP_000223.1	Q5U0N0
	SGCB	NM_001440519.1		c.28G>T	p.Glu10*	stop_gained	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-380G>T		5_prime_UTR	Exon 1 of 7	NP_001427449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.28G>T	p.Glu10*	stop_gained	Exon 1 of 6	ENSP00000370839.6	Q16585-1
	SGCB	ENST00000899666.1		c.28G>T	p.Glu10*	stop_gained	Exon 1 of 6	ENSP00000569725.1
	SGCB	ENST00000912466.1		c.28G>T	p.Glu10*	stop_gained	Exon 1 of 5	ENSP00000582525.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000264 AC: 3 AN: 1135578 Hom.: 0 Cov.: 31 AF XY: 0.00000182 AC XY: 1 AN XY: 548368

African (AFR) AF: 0.0000421 AC: 1 AN: 23754

American (AMR) AF: 0.00 AC: 0 AN: 17662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16950

East Asian (EAS) AF: 0.00 AC: 0 AN: 24710

South Asian (SAS) AF: 0.00 AC: 0 AN: 35138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3098

European-Non Finnish (NFE) AF: 0.00000212 AC: 2 AN: 945512

Other (OTH) AF: 0.00 AC: 0 AN: 45104

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2E (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.27	N
PhyloP100		0.61
Vest4		0.36
GERP RS		2.9
PromoterAI		0.098	Neutral
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1448040082; hg19: chr4-52904398;